A fundamental tenet of inheritance in sexually reproducing organisms such as humans and laboratory mice is that genetic variants combine randomly at fertilization, thereby ensuring a balanced and statistically predictable representation of inherited variants in each generation. This principle is encapsulated in Mendel’s First Law. But exceptions are known. With transmission ratio distortion (TRD), particular alleles are preferentially transmitted to offspring without reducing reproductive productivity. Preferential transmission usually occurs in one sex but not both and is not known to require interactions between gametes at fertilization. We recently discovered, in our work in mice and in other reports in the literature, instances where any of 12 mutant genes bias fertilization, with either too many or too few heterozygotes and too few homozygotes, depending on the mutant gene and on dietary conditions. Although such deviations are usually attributed to embryonic lethality of the under-represented genotypes, the evidence is more consistent with genetically-determined preferences for specific combinations of egg and sperm at fertilization that results in genotype bias without embryo loss. These genes and diets could bias fertilization in at least three not mutually exclusive ways. They could trigger a reversal in the order of meiotic divisions during oogenesis so that the genetics of fertilizing sperm elicits preferential chromatid segregation, thereby dictating which allele remains in the egg versus the 2nd polar body. Bias could also result from genetic- and diet-induced anomalies in polyamine metabolism on which function of haploid gametes normally depends. Finally, secreted and cell-surface factors in female reproductive organs could control access of sperm to eggs based on their genetic content. This unexpected discovery of genetically-biased fertilization in mice could yield insights about the molecular and cellular interactions between sperm and egg at fertilization, with implications for our understanding of inheritance, reproduction, population genetics, and medical genetics.